Synthesis and trypanocidal action of new adamantane substituted imidazolines† Ana Koperniku, a Ioannis Papanastasiou, a George B. Foscolos, * a Andrew Tsotinis, a Martin C. Taylor b and John M. Kelly b Introduction of the hydrophobic substituents cyclopentyl, cyclohexyl and phenyl into adamantane imidazolines was accomplished with the synthesis of compounds 4. Members of this series were found to display a range of activities against bloodstream forms of Trypanosoma brucei. Introduction Human African trypanosomiasis (HAT) is caused by tsetse y transmitted protozoan parasites of the Trypanosoma brucei species complex. HAT is endemic in several areas of Sub- Saharan Africa and subject to epidemic outbreaks. Drugs used to treat 1 HAT are thought to target a range of biological mole- cules. Elfornithine 2,3 is a specic irreversible inhibitor of the rst step in polyamine biosynthesis, which is the formation of putrescine from ornithine by ornithine decarboxylase. Eorni- thine is relatively expensive and requires administration over 14 days, under medical supervision. Suramin 4,5 is a large polyanion which exerts inhibitory activity on a variety of enzymes involved in several protozoan metabolic pathways. Melarsoprol 6,7 and its metabolite melarsen oxide inhibit many enzymes and substrates that contain vicinal thiol groups, e.g. trypanothione, and disrupt the intracellular thiol-redox balance in T. brucei. Melarsoprol is extremely toxic, with reactive encephalopathy killing up to 5% of patients. Diamidines 8–10 are nucleic acid binding drugs that target the kinetoplast. The trypanocidal activity of pentamidine is the result of selective accumulation leading to multiple lethal effects, rather than a single effect on a specic “diamidine target”. More recently, nifurtimox–eorni- thine combination therapy (NECT) has been introduced and has led to some improvements in treatment. 1 Other promising drug targets are N-myristoyltransferase, 11 protozoan caspases 12 and kinases. 13 It has been reported that various anti-Infuenza A virus ami- noadamantane derivatives, 14 e.g. rimantadine and to a lesser extent amantadine, are effective against the bloodstream forms of T. brucei. These adamantane amino derivatives readily cross the BBB and are well absorbed by the gastrointestinal tract. 15 Furthermore, other adamantane derivatives with hydrophobic substituents on the adamantane ring show increased trypano- cidal activity. 16 We have previously reported 17 the synthesis of compounds 1 and 2 (Fig. 1). The non-spiro analogues 2 were found to be potent against bloodstream form T. brucei. Fig. 1 Amantadine, rimantadine, adamantane analogues 1, 2 and 3. Fig. 2 5-(3-Substituted-1-adamantyl)-2-imidazolines 4a–s. Cite this: Med. Chem. Commun., 2013, 4, 856 Received 13th March 2013 Accepted 31st March 2013 DOI: 10.1039/c3md00081h www.rsc.org/medchemcomm a Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, 157 71 Athens, Greece. E-mail: gfosc@pharm.uoa.gr; Fax: +30 210 7274747; Tel: +30 210 7274527 b Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. E-mail: john.kelly@lshtm.ac.uk; Fax: +44 (0)207 6368739; Tel: +44 (0)207 9272330 † Electronic supplementary information (ESI) available: Experimental data for the compounds, materials and methods for pharmacological assay. See DOI: 10.1039/c3md00081h 856 | Med. Chem. Commun., 2013, 4, 856–859 This journal is ª The Royal Society of Chemistry 2013 MedChemComm CONCISE ARTICLE Published on 02 April 2013. Downloaded by The University of British Columbia Library on 24/06/2015 15:10:17. View Article Online View Journal | View Issue